Tuberculosis (TB) is a persistent lung infection that ranks as one of the most serious threats to world health today. The 2-3 million deaths attributed yearly to the disease, as well as the emergence drug-resistant Mycobacterium tuberculosis (MTB) strains, urgently call for the development of new therapies to treat TB. Indeed, the threat of drug-resistant MTB as a bioterrorism agent has led to it's listing as a NIAID Category C Priority Pathogen for biodefense research. We have isolated novel MTB mutants with lesions in individual genes that are required for normal growth during acute infection. In particular, we have identified the first specialized protein secretion system in MTB, which we have named the Snm pathway. Our initial results have led us to the hypothesis that proteins secreted by this pathway interact with macrophages to specifically inhibit innate macrophage response to infection. The studies proposed here give us the opportunity to test this model and thus understand the molecular details of host-pathogen interactions critical during the early stages of MTB infection. Specifically, we will identify all of the substrates secreted by the Snm system and determine their role in virulence. We will study a subset of Snm substrates that are required for manipulating macrophage responses and identify the host-pathogen interactions mediated by these virulence molecules. Finally, we will probe the impact of the Snm pathway on the global transcriptional response of macrophages to MTB infection. Because components of the Snm pathway are conserved in many other bacteria, understanding the common mechanisms of their function may lead to the development of inhibitors that could be useful for treating a broad range of infectious diseases. The results from these studies will direct our long-term plans to understand the role secreted proteins play in the struggle between MTB and the host. Ultimately, by understanding tuberculosis pathogenesis at the molecular level, we hope to aid in the discovery of new therapies to combat and eradicate this persistent infection.